Substituted 6H-1,3,4-thiadiazine-2-amines, the use thereof as anaesthetising, cardiovascular and hypometabolic agents, and pharmaceutical composition containing them

ABSTRACT

Substitued 6H-1,3,4-thiadiazin-2-amines of the following general formula:wherein Ar is phenyl optionally substituted with one or more chloro, bromo atoms, C1-C4 alkoxy, or C1-C4 alkyl groups; andrepresents a morpholino, thimomorpholino, piperidino, pyrrolidino, or hexamethylenimino moieties, the pharmaceutically acceptable salts thereof and the use of them anasethetic, cardiovascular and hypometabolic agents and pharmaceutical compositions containing them.

This application is a 371 of PCT/RU95/00284.

TECHNICAL FIELD

The present invention relates to novel 6H-1,3,4-thiadiazine-2-amines, totheir use in medicine or veterniary as anaesthetic, cardiovascular andhypometablic agents and to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Anaesthesia can generally be described as a state in which noxiousevents such as surgical procedures are rendered imperceptible by thebody, the state being accompanied either by loss of consciousness(general anaesthesia) or no loss of consciousness (local anaesthesia). Acomplete or general anaesthetic given by inhalation or intravenous routeproduces a state of profound sleep and loss of motor activity(hypnosis), analgesia, muscle relaxation and protection against theincrease in blood pressure and heart rate resulting from surgicalstress. Anaesthetics generally display hypometabolic activity andfrequently act as respiratory or cardiovascular depressants. Certainanesthetics can be used to produce deliberate hypotensive effects whichare very valuable in intracranial and other surgical procedures.Although a large number of agents having anaesthetic and cardiovascularactivity have been identified and/or commercialised, there is acontinuing need for new materials having hypomethabolic activity, whichare valuable for inducing sleep, reduction in motor activity,hypotension, bradycardiac, hypocoagulative, anti-aggregant and otherhypobiosis effects such as reduced oxygen consumption and reduced bodytemperature, which would be valuable for used in complex surgicalprocedures or in the treatment of life threatening and/or traumaticsituations such as brain stroke and myocardial infarction, and whichhave excellent potency, duration and CNS and cardiovascular toxicityprofiles with absence of side effects such as tremor, consulvions andirregular breathing and heart beat.

There is considerable body of data concering6-R-1,3,4-thiadiazin-2-amines (for reviews see [1-3]). Also a patentliterature provides data on myo-relaxant [4-7], sedative [8,9],spasmolytic [10-12] and other types of biological activity [3]. A numberof 5-aryl derivatives of 1,3,4-thiadiazines have been specificallydescribed in the art [14-20] as well as 6-alkyl and 6-phenyl analogsthereof [13 and 21]. The value of 6H-1,3,4-thiadiazin-2-amines ashypometabolic anaesthetic and cardiovascular agents has not hithertobeen recognised however. Moreever, many of these compounds areapparently novel and have not been previously described in theliterature.

The prior art on 6-R-1,3,4-thiadiazin-2-amines includes:

1. H. Beyer, Z. Chem., Bd. 9, S. 361, (1969).

2. S.V. Usoltseva, G.P. Andronnikova, and V.S. Mokreushin, Khim.Geterotsikl. Soedin., No 4, 435, (1991).

3. A.P. Novikova, N. M. Perova, and O. N. Chupakhin, Khim. Geterotsikl.Soedin., No 11, 1443, (1991)

4. W. D. Jones and F. P. Miller. US-A-4,309,426 (1982).

5. W. D. Jones and F. P. Miller. BE-A-884,991 (1980).

6. W. D. Jones and F. P. Miller. DE-A-3,042,295 (1982).

7. FR-A-2,493,844 (1982).

8. US-A-4,272,532 (1981).

9. F. P. Miller and W. D. Jones. BE-A-884,990 (1980).

10. W. D. Jones and F. P. Miller. DE-A-3,031,703 (1981).

11. Fisons PLC, Japan Kokai, Tokyo Koho JP-A-6253976.

12. W. P. Pfeiffer and E. Bulka, DD-A-220311 (1985).

13. N. Yoshida, K. Tanaka, and Y. Iizuka. Japan Kokai 7488889 (1974).

14. L. N. Rasina, O. N. Chupakhin and M. V. Chibiryak. Radiobiologiya,30(2), 162-5 (1990).

15. A. V. Belik et al, Khim.-Farm. Zh., 26(3), 62-64 (1992).

16. N. M. Perova et al, Khim. Geterotsikl. Soedin., No 4, 565-6 (1993).

17. E Bulka and W. D. Pfeiffer. DD-A-288824.

18. W. D. Pfeiffer and E Bulka, Synthesis, No 7, 485-486 (1977).

19. T. Werner et al, US-A-4,940,790 (1990).

20. A. P. Novikova et al, SU-A-1726478.

21. E. Bulka et al, DD-A-228248.

SUMMARY OF THE INVENTION

According to one aspect of the invention, there is provided the use ofsubstitued 6H-1,3,4-thiadiazin-2-amines of the following general formulaas anaesthetic, cardiovascular and hypometabolic agents:

wherein Ar is phenyl optionally substituted with one or more chloro,bromo atoms, C₁-C₄ alkoxy or C₁-C₄ alkyl groups; and wherein

represents a morpholino, thiomorpholino, piperidino, pyrrolidino, orhexamethylenimino moiety.

According to the further aspect of the invention, there are providedpharmaceutical composition which includes one ore more of substituted6H-1,3,4-thiadiazin-2-amines as defined above or pharmaceuticallyacceptable salts thereof.

According to the still further aspect of the invention, there areprovided certain novel substituted 6H-1,3,4-thiadiazin-2-amines of thegeneral formula set out above. Novel compounds of this class includecompounds in which

represents thiomorpholino moiety; compounds in which Ar is phenylsubstituted with one or more bromo atoms, C₁-C₄ alkoxy or C₁-C₄ alkylgroups, and

represents piperidino, pyrrolidino moiety; and compounds in which Ar isphenyl substituted at the 2 or 3 positions with one or more bromo atoms,C₁-C₄ alkoxy or C₁-C₄ alkyl groups, and

represents morpholino.

DISCLOSURE OF THE INVENTION

1,3,4-Thiadiazines suitable for the use according to the presentinvention contain at the 5 position of the thiadiazine ringunsubstituted phenyl or phenyl substituted with one or more straight orbranched chain C₁-C₄ alkyl, alkenyl, alkoxy or acyloxy groups, or one ormore hydroxy groups or halogen atoms. In preferred compounds, Arrepresents unsubstituted phenyl or phenyl substituted with one or morealkyl, alkoxy groups, or chloro or bromo atoms. Moreover said compoundsare substituted at the 2 position of the thiadiazine ring with acycloalkylimine moiety, preferably selected from morpholino,thiomorpholino, piperidino, pyrrolidino and hexamethylenimino.

The invention further relates to a process for the preparation of the1,3,4-thiadiazines described herein in with an α-haloarylalkanone havingthe formula Ar—CO—CH(R¹)X is reacted with a thiosemicarbazide of formula

wherein X is halo, preferably chloro or bromo, and Ar, R¹ and

are as defined above.

According to the present invention the 1,3,4-thiadiazines may beisolated and/or used in free from or converted into additive salts withpharmacologically acceptable mineral or organic acids. Suitable for thepreparation of acid addition salts are, for example, mineral acids, suchas hydrobromic acid, hydrochloric acid, sulfuric acid or phosphoricacid; organic carboxylic acids, such as acetic acid, lactic acid, maleicacid, fumaric acid, oxalic acid, tartaric acid, citric acid or gluoconicacid; or organic sulfonic acids, such as benzenesulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonicacid and cyclohexylamidosulfonic acid.

The α-haloarylalkanone used as starting materials in the manufacture ofthe thiadiazines described above are known from the literature or may beprepared starting from arylalkanones by the reaction with a suitablehalogenating agent according to the methods described in Houben-Weyl,Vol. E4 (1960), pp. 171-189. Suitable compounds are, for example,α-bromarylethanones in which aryl may be selected from phenyl andsubstituted phenyl and prepared by halogenating the correspondentsubstituted 1-arylalkanoes with bromine or copper (II) bromide accordingto the method of King and Ostrum, J. Org. Chem. 29 (1964), pp.3459-3461.

The substituted thiosemicarbazides which are used as starting materialsare generally known in the art or they may be prepared by the methodsdescribed in Houben-Weyl, Vol. E4, pp. 506-515, and by K. Jensen et al.,Acta Chem. Scand. 22 (1968), pp. 1-50. Thus, the thiosemicarbazides maybe obtained by adding hydrazine to isothiocyanates or by the reaction ofsuitable N,N-di-substituted thiocarbamoyl chlorides with hydrazine or bythe reaction of ethyl dithiocarbarates of formula

with hydrazine. In order to avoid interfering side reactions, saidpreparations are advantageously carried out in aprotic solvents, suchas, for example, chloroform, tetrachloromethane, diethyl ether ordioxan.

The reaction of α-haloarylalkanones with thiosemicarbazide isexpediently carried out using equimolar amounts of the two reactants ina solvent or in a diluent which are inert towards the reagents. Suitablefor this purpose are, in particular, lower alcohols, such as methanol,ethanol, n-propanol, isopropanol and the various butanols, orethylacetate, and mixtures thereof, however ethanol is preferable. Thereaction is generally carried out at temperatures in the range fromabout 20° C. to the temperature of the reflux of the reaction mixture,preferably at about 20° C. to 70° C. Depending on the reactivity of thereagents, the type of the reaction medium and the reaction temperature,reaction time may be in the range from about 5 minutes to 2 hours. Thefinal products usually recrystallize in analytically pure form on slowcooling of the reaction mixture.

Depending on their solubility the compounds may be administered eitherby oral route or via parenteral injection in the forms of theirsolutions. They may be administered either alone, for example in theform of microcapsules, as well as in mixtures with one another or incombination with suitable adjuvants and/or excipients.

The present invention further relates to pharmaceutical compositionswhich comprise at least one of thiadiazine compounds as defined above,or one of acid addition salts thereof, and which contain at least one ofsaid active compounds with pharmaceutically suitable and physiologicallyacceptable excipients, diluents and/or other adjuvants. Suitable solidor liquid galenic formulations include, for example, granules, powders,coated tablets, tablets, (micro) capsules, suppositories, syrups,elixirs, suspensions, emulsions, drops of injectable solutions, and alsopreparations having a protracted release of active compound, in thedisintegrants, binders, coating agents, swelling agents, glidants,lubricants, flavors, sweeteners or solubilizers are usually used.Suitable adjuvants include, for example, magnesium carbonate, titaniumdioxide, lactose, mannitol and other sugars, talc, lactalbumin,gelatine, starch, cellulose and derivatives thereof, animal andvegetable oils, polyethylene glycols and solvents such as sterile waterand monohydric or polyhydric alcohols, for example glycerol.

The pharmaceutical preparations are preferably manufactured andadministered for treating in dosage units, each of them contains asactive component a certain dose of at least one of thiadiazine compoundsand/or at least one of corresponding acid addition salts thereof. In thecase of injectable solutions, the thiadiazine is preferably administeredin dosages in the range from about 10 to about 600, preferably fromabout 20 to about 500, more preferably from about 30 to about 400 mg/kg.

Compounds suitable for use herein are represented by the followingexamples:

1. 2-Morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide,

2. 2-Morpholino-5-phenyl-6H-1,3,4-thiadiazine, mesilate,

3. 2-Morpholino-5-(4-chlorophenyl)-6H-1,3,4-thiadiazine, hydrobromide,

4. 2-Morpholino-5-(3-bromophenyl)-6H-1,3,4-thiadiazine, hydrobromide,

5. 2-Thiomorpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide,

6. 2-Thiomorpholino-5-phenyl-6H-1,3,4-thiadiazine, mesilate,

7. 2-Thiomorpholino-5-(4-ethoxypenyl)-6H-1,3,4-thiadiazide,hydrobromide,

8. 2-Thiomorpholino-5-(3-bromophenyl)-6H-1,3,4-thiadiazine,hydrobromide,

9. 2-Thiomorpholino-5-(4-methoxypehnyl)-6H-1,3,4-thiadiazine,hydrobromide,

10. 2-Thiomorpholino-5-(2-chlorophenyl)-6H-1,3,4-thiadiazine,hydrobromide,

11. 2-Thiomorpholino-5-(4-chlorophenyl)-6H-1,3,4-thiadiazine,hydrobromide,

12. 2-Hexamethylenimino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide,

13. 2-Piperidino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide,

14. 2-Pyrrolidino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide,

15. 2-Hexamethylenimino-5-(4-bromophenyl)-6H-1,3,4-thiadiazine,hydrobromide,

16. 2-Hexamethylenimino-5-(4-chlorophenyl)-6H-1,3,4-thiadiazine,hydrobromide,

17. 2-Hexamethylenimino-5-(4-bromophenyl)-6H-1,3,4-thiadiazine,mesilate,

18. 2-Morpholino-5-(2-chlorophenyl)-6H-1,3,4-thiadiazine, hydrobromide.

EXAMPLES

All compounds herein were obtained in 60-80% yields by condensation ofα-naloketones with the corresponding 4-substituted thiosemicarbazides,proceeding smoothly on heating in ethanol. Evidence for the structure ofthe compounds is provided by their spectral data (UV, IR, ¹H NMR); theirpurity is confirmed by thin-layer chromatography and elemental analysis.

Example 1 2-Morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide.

The compound 1 was prepared by heating of 2 g (0.01 mole) ofα-bromacetophenone with 1.6 g (0.01 mole) of morpholide ofthiocarbazinic acid in 20 ml of absolute ethanol for 30 minutes. Theproduct obtained after cooling was filtered off and recrystallized twicewith active charcoal. Yield 1.8 g (75%). M.p. 191-192° C. R_(f)=0.35(eluent: butanol-acetic acid-water 4:1:5). Found, %: C 45.7; H 4.7; N12.1. C₁₃H₁₆BrN₃OS. Calcualted %: C 45.6; H 4.7; N 12.3. ¹H NMR,DMSO-d₆, δ, ppm: 3.85 (8H, m, morpholino); 4.45 (2H, s, CH₂S); 7.45-8.1(5H, m, C₆H₅).

Example 2 2-Morpholino-5-phenyl-6H-1,3,4-thiadiazine, mesilate

Methanesulfonic acid, 0.4 g (0.004 mole), was added dropwise to asolution of 1 g (0.004 mole) of the compound 1 in 70 ml of dry ether. Acolourless precipitate formed after 20 minutes of stirring was filteredoff and recrystallized from absolute ethanol. Yield 1.2 g (88%). M.p.173-174° C. R_(f)=0.38 (eluent: butanol-acetic acid-water 4:1:5). Found,%: C 47.0; H 5.5; N 11.6 C₁₄H₁₉N₃O₄S₂. Calculated, %: C 47.1; H 5.3; N11.8. ¹H NMR, DMSO-d₆, δ, ppm: 2.30 (3H, s, SCH₃); 3.82 (8H, m,morpholino); 4.29 (2H, s, CH₂S); 7.4-8.0 (5H, m, C₆H₅).

Example 3 2-Morpholino-5-(4-chlorophenyl)-6H-1,3,4-thiadiazine,hydrobromide.

The compound 3 was prepared in the same manner as in Example 1. Yield67%. M.p. 242-243° C. R_(f)=0.37 (eluent: butanol-acetic acid-water4:1:5). Found, %: C 41.7; H 4:1; N 11.4. C₁₃H₁₅BrClN₃OS. Calculated, %:C 41.7; H 4.0; N 11.2. ¹H NMR, DMSO-d₆, δ, ppm: 3.85 (8H, m,morpholino): 4.40 (2H, s, CH₂S); 7.70 and 7.90 (4H, dd, C₆H₄).

Example 4 2-Morpholino-5-(3-bromophenyl)-6H-1,3,4-thiadiazine,hydrobromide.

The compound 4 was prepared in the same manner as in Example 1 startingfrom 3-bromo-α-bromoacetophenone and morpholide of thiocarbazinic acid.Yield 70%. M.p. 191-192° C. R_(f)=0.3 (elunet: butanol-acetic acid-water4:1:5). Found, %: C 37.4; H 3.6 C₁₃H₁₅Br₂N₃OS. Calculated, %: C 37.1; H3.6. ¹H NMR, DMSO-d₆, δ, ppm: 3.80 (8H, m, morpholino); 4.29 (2H, s,CH₂S); 7.3-8.2 (4H, m, C₆H₄).

Example 5 2-Thiomorpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide.

The compound 5 was prepared by heating of 2 g (0.01 mole) ofα-bromacetophenone with 1.8 g (0.01 mole) of thiomorpholinide ofthiocarbazinic acid in 25 ml of absolute ethanol in the presence of 1.2ml of concentrated HBr for 20 minutes. The mixture was cooled with iceto give a yellow precipitate which was filtered off, recystallized fromabsolute ethanol and dried. Yield 2.8 g (78%). M.p. 183-184° C.R_(f)=0.51 (eluent: butanol-acetic acid-water 4:1:5). Found %: C 43.7; H4.6; N 11.7. C₁₃H₁₆BrN₃S₂. Calculated, %: C 43.6; H 4.5; N 11.7. ¹H NMR,DMSO-d₆, δ, ppm: 2.9 (4H, m, N(CH₂)₂, thiomorpholino); 4.15 (4H, m,S(CH₂)₂, thiomorpholino); 4.42 (2H, s, CH₂S); 7.4-8.1 (5H, m C₆H₅).

Example 6 2-Thiomorpholino-5-phenyl-6H-1,3,4-thiadiazine, mesilate.

Methanesulfonic acid, 0.4 g (0.004 mole), was added dropwise to asolution of 1 g (0.004 mole) of the compound 5. A colourless crystallineproduct obtained after 15 minutes of stirring was filtered off andrecystallized from a mixture of absolute ethanol and dry ether 1:4.Yield 1.2 g (89%). M.p. 160-160° C. R_(f)=0.43 (eluent: butanol-aceticacid-water 4:1:5). Found, %: C 44.9; H 5.0; N 11.4. C₁₄H₁₉N₃O₃S₃.Calculated, %: C 45.0; H 5.1; N 11.3. ¹H NMR, DMSO-d₆, δ, ppm: 2.30 (3H,s, SCH₃); 2.88 [4H, m, N(CH₃)₂, thiomorpholino]; 4.15 [4H, m, S(CH₂)₂,thiomorpholino]; 4.31 (2H, s, SCH₂); 7.4-8.1 (5H, m, C₆H₅).

Example 7 2-Thiomorpholino-5-(4-ethoxyphenyl)-6H-1,3,4-thiadiazine,hydrobromide.

The compound 7 was prepared by heating of 0.7 g (0.003 mole) ofα-bromo-4-ethoxyacetophenone with 0.5 g (0.003 mole) of thiomorpholideof thiocarbazinic acid in 15 ml of absolute ethanol in the presence of0.3 ml of concentrated HBr for 20 minutes. The mixture was cooled withice to give a yellow precipitate which was filtered off, recystallizedfrom absolute ethanol and dried. Yield 0.8 g (70%). M.p. 169-170° C.R_(f)=0.33 (eluent: butanol-acetic acid-water 4:1:5). Found, %: C 45.0;H 5.2; N 10.3. C₁₅H₂₀BrN₃OS₂. Calculated, %: C. 44.8; H 5.0; N 10.4. ¹HNMR, DMSO-d₆, δ, ppm: 1.32 (3H, t, CH₃); 2.88 [4H, m, N(CH₂)₂,thiomorpholino]; 4.12 [4H, m, S(CH₂)₂, thiomorpholino]; 4.26 (2H, q,OCH₂—); 4.37 (2H, s, CH₂S); 7,5 (4H, dd, C₆H₄).

Example 8 2-Thiomorpholino-5-(3-bromophenyl)-6H-1,3,4-thiadiazine,hydrobromide.

The compound 8 was prepared by heating of 0.8 g (0.003 mole) ofα-bromo-3-bromoacetophenone with 0.5 g (0.003 mole) of thiomorpholinideof thiocarbazinic acid in 20 ml of absolute ethanol in the presence of0.3 ml of concentrated HBr for 15 minutes. The mixture was cooled withice to give a yellow precipitate which was filtered off, recrystallizedfrom absolute ethanol and dried. Yield 0.75 g (64%). M.p. 198-199° C.R_(f)=0.23 (eluent: butanol-acetic acid-water 4:1:5). Found, %: C 36.3;H 3.6. Si 9.8. C₁₃H₁₅Br₂N₃S₂. Calculated, %: C 35.7; H 3.4; N 9.6. ¹HNMR, DMSO-d₆, δ, ppm: 2.88 [4H, m, N(CH₂)₂, thiomorpholino]; 4.15 [4H,m, S(CH₂)₂, thiomorpholino]; 4.33 (2H, s, CH₂S); 7.35-8,14 (4H, m,C₆H₁₄).

Example 9 2-Thiomorpholino-5-(4-methoxyphenyl)-6H-1,3,4-thiadiazine,hydrobromide

The compound 9 was prepared in the same manner as in Example 5 startingfrom 4-methoxyphenyl-α-bromoaceto-phenone and thiomorpholide ofthiocarbazinic acid. Yield 77%. M.p. 201-202° C. R_(f)=0.35 (eluent:butanol-acetic acid-water 4:1:5). Found, %: C 43.6; H 4.7; N 10.9.C₁₄H₁₈BrN₃OS₂. Calculated, %: C 43.3; H 4.6: N 10.8. ¹H NMR, DMSO-d₆, δ,ppm: 2.88 [4H, m, N(CH₂)₂, thiomorpholino]; 3.85 (3H, s, OCH₃); 4.12[4H, m, S(CH₂)₂, thiomorpholino]; 4.32 (2H, s, Ch₂S); 7.5 (4H, dd,C₆H₄).

Example 10 2-Thiomorpholino-5-(2-chlorophenyl)-6H-1,3,4-thiadiazine,hydrobromide

The compound 10 was prepared by heating of 0.7 g (0.003 mole) ofα-bromo-2-chloroacetophenone with 0.5 g (0.003 mole) of thiocarbazinicacid thiomorpholide in 30 ml of absolute ethanol in the presence of 0.3ml of concentrated HBr for 30 minutes. After cooling with ice 30 ml dryether was added to the reaction mixture, yielding a yellow precipitatewhich was filtered off, recystallized from absolute ethanol and dried.Yield 0.85 g (71%). M.p. 190-191° C. R_(f)=0.38 (eluent: butanol-aceticacid-water 4:1:5). Found, %: C 39.8; H 4.2; N 10.6. C₁₃H₁₅BrCIN₃S₂.Calculated, %: C 39.7; H 3.8; N 10.7. ¹H NMR, DMSO-d₆, δ, ppm: 2.88 [4H,m, N(CH₂)₂, thiomorpholino]; 4.15 [4H, m, S(CH₂)₂, thiomorpholino]; 4.25(2H, s, CH₂S); 7.4-7.8 (4H, dd C₆H₄).

Example 11 2-Thiomorpholino-5-(4-chlorophenyl)-6H-1,3,4-thiadiazine,hydrobromide

The compound 11 was prepared by heating of 2.3 g (0.01 mole) ofα-bromo-4-chloroacetophenone with 1.8 g (0.01 mole) of thiomorpholide ofthiocarbazinic acid in 50 ml of absolute ethanol for 25 minutes. Themixture was cooled with ice to give a yellow precipitate which wasfiltered off, recrystallized from absolute ethanol and dried. Yield 3.0g (77%). M.p. 201-202° C. R_(f)=0.50 (eluent: butanol-acetic acid-water4:1:5). Found, %: C 40.0; H 4.2; N 10.06. C₁₃H₁₅BrClN₃S₂. Calculated, %:C 39.7; H 3.8; N 10.7. ¹H NMR, DMSO-d₆, δ, ppm: 2.88 [4H, m, N(CH₂)₂,thiomorpholino]; 4.18 [4H, m, S(CH₂)₂, thiomorpholino]; 4.39 (2H, s,CH₂S); 7.3 (4H, dd, C₆H₄).

Example 12 2-Hexamethylenimino-5-phenyl-6H-1,3,4-thiadiazine,hydrobromide

The compound 12 was prepared in the same manner as in Example 5 startingfrom α-bromoacetophenone and 4,4-hexamethyleniminothiosemicarbazide.Yield 68%. M.p. 203-204° C. R_(f)=0.42 (eluent: butanol-aceticacid-water 4:1:5). Found, %: C 50.6; H 5.6; N 11.6. C₁₅H₂₀BrN₃S.Calculated, %: C 50.8; H 5.6; N 11.9. ¹H NMR, DMSO-d₆, δ, ppm: 1.4-2.2[8H, m, (CH₂)₄, hexamethylenimino]; 3.7-4.2 [4H, m, N(CH₂)₂,hexamethylenimino]; 4.48 (2H, s, CH₂S); 7.5-8.1 (5H, m, C₆H₅).

Example 13 2-Piperidino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide

The compound 13 was prepared in the same manner as in Example 5 startingfrom α-bromoacetophenone and 4,4-pentamethyleniminothiosemicarbazide.Yield 68%. M.p. 230-232° C. R_(f)=0.7 (eluent: butanol-acetic acid-water4:1:5). Found, %: C 49.5, H 5.4; N 12.4. C₁₄H₁₈BrN₃S. Calculated, %: C49.4, H 5.3, N 12.4. ¹H NMR, DMSO-d₆, δ, ppm: 1.5-2.2 [6H, m, (CH₂)₄,piperidino]; 3.5-3.8 [4H, m, N(CH₂)₂, piperidino]; 4.35 (2H, s, CH₂S);7.2-8.1 (5H, m, C₆H₅).

Example 14 2-Pyrrolidino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide

The compound 14 was prepared in the same manner as in Example 5 startingfrom α-bromoacetophenone and 4,4-tetramethyleniminothiosemicarbazide.Yield 78%. M.p. 182-183° C. R_(f)=0.49 (eluent: butanol-aceticacid-water 4:1:5). Found, %: C 47.6; H 4.9; N 12.9. C₁₃H₁₈BrN₃S.Calculated, %: C 47.9; H 5.0; N 12.9. ¹H NMR, DMSO-d₆, δ, ppm: 2.1 [4H,m, (CH₂)₂, pyrrolidino]; 3.7 [4H, m, N(CH₂)₂, pyrrolidino]; 4.45 (2H, s,CH₂S); 7.4-8.0 (5H, m, C₆H₅).

Example 15 2-Hexamethylenimino-5-(4-bromophenyl)-6H-1,3,4-thiadiazine,hydrobromide

The compound 15 was prepared in the same manner as in Example 5 startingfrom α-bromo-4-bromoacetophenone and4,4-hexamethyleniminothiosemicarbazide. Yield 75%. M.p. 201-14 203° C.R_(f)=0.38 (eluent: butanol-acetic acid-water 4:1:5). Found, %: C 42.0;H 4.6; N 9.4. C₁₅H₁₉Br₂N₃S. Calculated, %: C 41.6; H 4.4; N 9.7. ¹H NMR,DMSO-d₆, δ, ppm: 1.4-2.3 [3H, m, (CH₂)₄, hexamethylenimino]; 3.6-4.1[4H, m, N(CH₂)₂, hexamethylenimino]; 4.5 (2H, s, CH₂S); 7.8 (4H, dd,C₆H₄).

Example 16 2-Hexamethylenimino-5-(4-chlorophenyl)-6H-1,3,4-thiadiazine,hydrobromide

The compound 16 was prepared in the same manner as in Example 5 startingfrom α-bromo-4-chloroacetophenone and4,4-hexamethyleniminothiosemicarbazide. Yield 68%. M.p. 199-200° C.R_(f)=0.30 (eluent: butanol-acetic acid-water 4:1:5). Found, %: C 46.4;H 5.2; N 10.6. C₁₅H₁₉BrClN₃S. Calculated, %: C 46.3; H 4.9; N 10.8. ¹HNMR, DMSO-d₆, δ, ppm: 1.4-2.3 (8H, m, (CH₂)₄, hexamethylenimino);3.6-4.2 [4H, m, N(CH₂)₂, hexamethylenimino]; 4.47 (2H, s, CH₂S); 7.75(4H, dd, C₆H₄).

Example 17 2-Hexamethylenimino-5-(4-bromophenyl)-6H-1,3,4-thiadiazine,mesilate

Methanesulfonic acid, 0.4 g (0.004 mole), was added dropwise to thesolution of 1.5 g (0.004 mole) of the compound 15, and the reactionmixture was stirred at room temperature for 30 minutes. A colourlesscrystalline product obtained was filtered off and recrystallized fromabsolute ethanol. Yield 1.7 g (89%). M.p. 201-202° C. R_(f)=0.26(eluent: butanol-acetic acid-water 4:1:5). Found, %. C. 42.7; H 4.9; N14.1. C₁₆H₂₂BrN₃O₃S₂. Calculated, %: C. 42.9; H 4.9; N 14.3 ¹H NMR,DMSO-d₆, δ, ppm: 1.38-2.05 [8H, m, (CH₂)₄, hexamethylenimino]; 2.35 (3H,s, SCH₃); 3.6-4.0 [4H, m, N(CH₂)₂, hexamethylenimino]; 4.35 (2H, s,CH₂S); 7.80 (4H, dd, C₆H₄).

Example 18 2-Morpholino-5-(2-chlorophenyl)-6H-1,3,4-thiadiazine,hydrobromide

The compound 18 was prepared by heating of 1.2 g (0.005 mole) ofα-bromo-2-chloroacetophenone with 0.8 g (0.005 mole) of morpholide ofthiocarbazinic acid in 30 ml of absolute ethanol for 20 minutes. Themixture was cooled with ice to form a yellow precipitate which wasfiltered off, recrystallized from absolute ethanol and dried. Yield 1.4g (76%). M.p. 204-205° C. R_(f)=0.32 (eluent: butanol-acetic acid-water4:1:5). Found, %: C 41.6; H 4.1; N 11.3. C₁₃H₁₅BrClN₃OS. Calculated, %:C 41.4; H 4.0; N 11.2. ¹H NMR, DMSO-d₆, δ, ppm: 3.85 [8H, m, (CH₂)₂,morpholino]; 4.25 (2H, s, SCH₂); 7.4-7.9 (4H, m, C₆H₄).

EXPERIMENTAL BIOLOGICAL PART

The hypometabolic activity of the compounds utilised herein wasdemonstrated as follows. In all cases tests were carried out on mice ofthe BALB line of 3-4 month age. Non-toxic doses of compounds under testvarying from 60 to 400 mg/kg were used in all experiments. In the caseof water-soluble compounds, aqueous solutions of the test compounds wereinjected intraperitoneally (i.p.), while water-insoluble compounds wereintroduced orally (p.o.).

In order to demonstrate the effect of the compounds herein on bodytemperature and oxygen consumption, in-vivo experiments were run using5-6 mice per dosage.

Rectal temperature changes (absolute magnitues in ° C.) were measuredusing a medicinal electrothermometer TREM-1 (Table 1). The rate ofoxygen consumption was monitored by measuring concentration of oxygen ina closed testing unit with optic-acoustic gas analyser MN 5130. The dataon oxygen consumption are given in percents relative to the startingcontent of oxygen taken as 100%. (Table 2).

When used in non-toxic doses all compounds were found to decrease rectaltemperature in the range from 3 to 15° C., depending on the structure,dosage and method of introduction. It has been established that some ofthe tested compounds show sharp drop in body temperature (7-8 ° C. per30 minutes) while others demonstrate only moderate effect (7-10° C. per3 hours) as illustrated in Table 1.

Compound 1 was dissolved in water (30 mg/ml) and injected into miceintraperitoneally in doses varying from 10 up to 365 mg/kg ({fraction(1/16)} LD₁₆-LD₅₀).

Rectal temperature of mice was followed in dynamics after 5, 15, 30, 60,120, 180, 240, 300, and 360 minutes (Table 3). The maximum change wasobserved with doses of 140 and 190 mg/kg, equal calculated andexperimental values of ½ LD₁₆, respectively, The maximum drop of bodytemperature (7-8° C.) at 140 mg/kg dosage was observed after 40-60minutes. The same decrease in temperature at 190 mg/kg dosage wasreached after 15 minutes; in 1.5 hours it reached 22-25° C. andmaintained this level over the next 5 hours, that is 13-17° C. below theinitial value. After one day, body temperature was restored to the valueof 94-96% of initial.

The behaviour of mice to injection of compound 1 at 140 mg/kg dosage isas follows:

5 minutes—decrease in motor activity, suppression of breathing; 15-180minutes—akinesia, mio-relaxation, lack of reflexes; 180-360minutes—restoration of motor activity. Importantly, the reduction inbody temperature at non-toxic dose levels was not accompanied by tremoror convulsions.

The effect of Compound 1 on oxygen consumption is tabulated in Table 3.

TABLE 1 Effects of 1,3,4-thiadiazines on body temperature in experimentson mice Dose, Time of measurements mg/kg in minutes Compound (mM/kg)Administration 0 30 60 90 1 190.0 (0.56) i.p. 39.2 26.9 23.5 21.4 2178.0 (0.50) i.p. 38.0 30.1 26.7 25.5 4 437.0 (1.00) p.o. 38.0 35.9 33.833.5 5 190.0 (0.53) i.p. 38.0 28.0 27.1 — 328.0 (0.96) p.o. 38.0 27.526.0 24.0 6 160.0 (0.43) i.p. 37.9 30.6 26.9 26.3 407.0 (1.0)  p.o. 37.734.0 33.4 32.6 8 435.0 (1.0)  p.o. 38.1 35.2 35.0 — Dose, Time ofmeasurements mg/kg in minutes Compound (mM/kg) Administration 120 180240 300 1 190.0 (0.56) i.p. 23.0 20.9 21.1 20.2 2 178.0 (0.50) i.p. 26.931.0 35.4 35.4 4 437.0 (1.00) p.o. 32.9 33.1 32.8 — 5 190.0 (0.53) i.p.25.0 23.3 23.6 — 328.0 (0.96) p.o. 24.0 — — — 6 160.0 (0.43) i.p. 25.827.4 28.9 30.9 7 407.0 (1.0)  p.o. 33.5 32.3 30.6 30.6 8 435.0 (1.0) p.o. 33.4 33.5 32.3 33.9

TABLE 2 Effects of Compound 1 on body temperature (T) and consumption ofoxygen (O₂) in experiments on mice Dose (1/2 LD₁₆) Time of measurementsmg/kg in minutes Compound (mM/kg) Index 0 5 15 30 60 1 190 (0.56) T 39.2 ± 0.1 34.9 ± 0.0 30.8 ± 0.2 26.9 ± 0.4 23.5 ± 0.2 O₂ 100 43 71.749.2 29.5 Dose (1/2 LD₁₆) Time of measurements mg/kg in minutes Compound(mM/kg) Index 90 120 180 240 300 1 190 (0.56) T  21.4 ± 0.2 23.0 ± 0.820.9 ± 0.1 21.1 ± 0.1 20.2 ± 0.0 100 47.5 36.9 55.3 99.6 151.6

TABLE 3 Dose effects of Compound 1 on body temperature (T) andconsumption of oxygen (O2) experiments on mice Dose mg/kg Time ofmeasurements in minutes (mM/kg) Index 0 10 20 30 40 60 365.0 (1.06) T 39.6 ± 0.1  35.4 ± 0.2 30.1 ± 0.2 27.2 ± 0.2 25.5 ± 0.2 23.3 ± 0.3 O₂100 ± 4.7  15.2 ± 3.1 15.8 ± 5.0 13.6 ± 3.4 13.3 ± 3.7 279.0 (0.82) T 38.9 ± 0.6  35.8 ± 0.1 30.2 ± 0.1 27.1 ± 0.1 24.7 ± 0.2 21.0 ± 0.1 O₂100 ± 5.2  32.6 ± 2.2 26.7 ± 2.2 20.7 ± 2.2  9.3 ± 5.1 190.0 (0.56) T 39.2 ± 0.1  34.9 ± 0.0 30.8 ± 0.2 26.9 ± 0.4 25.9 ± 0.3 23.5 ± 0.2 O₂ 100 ± 27.8 26.3 ± 9.8 71.7 ± 4.1 49.2 ± 8.2  29.5 ± 15.0 140.0 (0.41)T  37.9 ± 0.1  34.5 ± 0.2 32.6 ± 0.4 30.8 ± 0.2 30.2 ± 0.1 30.0 ± 0.1 O₂ 100 ± 21.7 26.3 ± 6.8 46.8 ± 4.7 32.2 ± 8.7 49.3 ± 9.8  70.0 (0.20) T 37.5 ± 0.2  36.2 ± 0.3 35.4 ± 0.5 34.5 ± 0.4 35.0 ± 0.9 35.6 ± 0.6 O₂35.0 (0.1) T  37.7 ± 0.2  37.2 ± 0.2 36.6 ± 0.4 35.9 ± 0.1 36.6 ± 0.137.0 ± 0.3 O₂ 100 ± 7.4   86.3 ± 13.1 73.6 ± 2.6 68.4 ± 8.0 70.4 ± 7.1 10.0 (0.05) T  37.5 ± 0.2  37.8 ± 0.1 37.4 ± 0.2 37.3 ± 0.1 37.5 ± 0.137.5 ± 0.1 O₂ 100 ± 6.9  94.0 ± 5.5 87.3 ± 9.9 78.2 ± 4.6  83.3 ± 18.1Dose mg/kg Time of measurements in minutes (mM/kg) Index 90 120 180 210240 270 365.0 (1.06) T  21.5 ± 0.2 20.9 ± 0.2 21.4 ± 0.1 21.2 ± 0.0 21.1± 0.0 21.4 ± 0.7 O₂ 13.1 ± 2.0 17.0 ± 3.4 11.2 ± 3.4  8.2 ± 2.0 279.0(0.82) T  20.0 ± 0.1 21.0 ± 0.3 21.2 ± 0.2 21.2 ± 0.1 20.8 ± 0.1 21.5 ±0.1 O₂ 10.9 ± 5.5  9.3 ± 5.9  9.3 ± 4.0 13.0 ± 8.7 190.0 (0.56) T  21.4± 0.2 23.0 ± 0.8 20.9 ± 0.1 21.4 ± 0.1 21.1 ± 0.1 20.8 ± 0.3 O₂ 47.5 ±6.8  36.9 ± 22.8 55.3 ± 9.1  99.6 ± 11.2 140.0 (0.41) T  31.5 ± 0.9 33.6± 0.7 35.2 ± 0.5 36.1 ± 0.4 36.5 ± 0.2 36.6 ± 0.2 O₂  43.6 ± 18.6  49.3± 15.4  78.9 ± 10.6 88.8 ± 9.8  70.0 (0.20) T  36.1 ± 0.2 37.0 ± 0.236.7 ± 0.6 36.9 ± 0.2 37.0 ± 0.1 36.6 ± 0.2 35.0 (0.1) T  37.3 ± 0.137.1 ± 0.3 36.9 ± 0.2 36.6 ± 0.1 36.9 ± 0.4 36.8 ± 0.1 O₂  72.1 ± 10.4 68.4 ± 11.2 78.4 ± 9.3 97.4 ± 5.6  10.0 (0.05) T  37.4 ± 0.2 36.9 ± 0.136.9 ± 0.2 36.4 ± 0.2 36.7 ± 0.2 36.7 ± 0.2 O₂  75.9 ± 19.3  95.6 ± 10.880.6 ± 9.9 92.6 ± 3.9 Dose mg/kg Time of measurements in minutes (mM/kg)Index 300 330 390 1140 1620 1980  36.5 (1.06) T  22.1 ± 0.0 21.5 ± 0.120.0 ± 0.2 20.8 ± 0.3 21.6 ± 0.1 22.1 ± 0.2 O₂ 18.4 ± 2.0 279.0 (0.82)T  21.3 ± 0.3 22.5 ± 0.3 19.4 ± 0.3 20.8 ± 0.4 22.6 ± 0.9 21.2 ± 0.3 O₂10.9 ± 1.0 190.0 (0.56) T  20.2 ± 0.2 19.8 ± 0.2 19.8 ± 0.2 36.9 ± 0.337.9 ± 0.4 36.9 ± 0.3 O₂ 151.6 ± 20.7 140.0 (0.41) T  36.9 ± 0.1 37.6 ±0.2 37.2 ± 0.2 O₂ 105.3 ± 20.5  70.0 (0.20) T  37.0 ± 0.1 37.2 ± 0.137.1 ± 0.1 O₂ 35.0 (0.1) T  36.9 ± 0.1 37.2 ± 0.2 37.1 ± 0.1 O₂ 85.1 ±3.8  10.0 (0.05) T  36.9 ± 0.1 36.8 ± 0.2 36.7 ± 0.2 O₂ 109.7 ± 8.8 

What is claimed is:
 1. A method for retarding metabolism in a patient so as to reduce the body temperature, oxygen intake or both of the patient, said method comprising administering to the patient an amount effective for said regulation of a 6H-1,3,4-thiadiazin-2-amine of the following formula:

wherein Ar is phenyl optionally substituted with one or more chloro, bromo atoms, C₁-C₄ alkoxy or C₁-C₄ alkyl groups; and

represents a morpholino, thiomorpholino, piperidino, pyrrolidino, or hexamethyenimino moiety, or a pharmaceutically acceptable salt thereof.
 2. A method as claimed in claim 1 wherein the 6H-1,3,4-thiadiazin-2-amine is selected from the consisting of group: 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine; 2-morpholino-5-(4-chlorophenyl)-6H-1,3,4-thiadiazine, 2-morpholino-5-(3-bromophenyl)-6H-1,3,4-thiadiazine; 2-thiomorpholino-5-phenyl-6H-1,3,4-thiadiazine; 2-thiomorpholino-5-(4-ethoxyphenyl)-6H-1,3,4-thiadiazine; 2-thiomorpholino-5-(3-bromophenyl)-6H-1,3,4-thiadiazine; 2-thiomorpholino-5-(4-methoxypenyl)-6H-1,3,4-thiadiazine; 2-thiomorpholino-5-(2-chlorophenyl)-6H-1,3,4-thiadiazine; 2-thiomorpholino-5-(4-chlorophenyl)-6H-1,3,4-thiadiazine; 2-hexamethylenimino-5-phenyl-6H-1,3,4-thiadiazine; 2-piperidono-5-phenyl-6H-1,3,4-thiadiazine; 2-pyrrolidino-5-phenyl-6H-1,3,4-thiadiazine; 2-hexamethylenimino-5-(4-bromophenyl)-6H-1,3,4-thiadiazine; 2-hexamethylenimino-5-(4-chlorophenyl)-6H-1,3,4-thiadiazine; 2-morpholino-5-(2-chlorophenyl)-6H-1,3,4-thiadiazine; and pharmaceutically acceptable salts thereof.
 3. A method as claimed in claim 1, wherein the 6H-1,3,4-thiadiazin-2-amine is administered to the patient in an amount effective to reduce the body temperature of the patient.
 4. A method as claimed in claim 1, wherein the 6H-1,3,4-thiadiazine-2-amine is administered to the patient in an amount effective to reduce the oxygen consumption of the patient. 